Chlordiazepoxide Hydrochloride and Clidinium Bromide
CHLORDIAZEPOXIDE HYDROCHLORIDE AND CLIDINIUM BROMIDE- chlordiazepoxide and clidinium bromide capsule
Heritage Pharmaceuticals Inc. d/b/a Avet Pharmaceuticals Inc.
WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS
; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS
- Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation (see WARNINGS and PRECAUTIONS and PRECAUTIONS, Drug Interactions).
- The use of benzodiazepines, including chlodiazepoxide hydrochloride, a component of chlordiazepoxide hydrochloride and clidinium bromide capsules, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing chlordiazepoxide hydrochloride and clidinium bromide capsules and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (see WARNINGS).
- The continued use of benzodiazepines, including chlordiazepoxide hydrochloride and clidinium bromide capsules, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of chlordiazepoxide hydrochloride and clidinium bromide capsules after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue chlordiazepoxide hydrochloride and clidinium bromide capsules or reduce the dosage (see WARNINGS and DOSAGE AND ADMINISTRATION).
Chlordiazepoxide hydrochloride and clidinium bromide capsules are a
fixed-combination of chlordiazepoxide hydrochloride, a benzodiazepine,
and clidinium bromide, an anticholinergic.
Each Chlordiazepoxide hydrochloride and clidinium bromide capsule
contains the active ingredients 5 mg chlordiazepoxide hydrochloride
and 2.5 mg clidinium bromide. Each capsule also contains the inactive
ingredients lactose monohydrate, pregelatinized starch, talc. Gelatin
capsule shells may contain titanium dioxide with the following dye
systems: D&C Yellow #10, FD&C Green #3 and gelatin. Imprinting ink is
composed of shellac, propylene glycol, black iron oxide, strong
ammonia solution and potassium hydroxide.
Chlordiazepoxide hydrochloride is 7-chloro-2-methylamino-5-phenyl-
3H-1,4-benzodiazepine 4-oxide hydrochloride. A colorless, crystalline
substance, it is soluble in water. It is unstable in solution and the
powder must be protected from light. The molecular weight is 336.22. The structural formula of chlordiazepoxide hydrochloride is as follows:
Clidinium bromide is a synthetic anticholinergic agent which has been
shown in experimental and clinical studies to have a antispasmodic and
antisecretory effects on the gastrointestinal tract. Structurally clidinium bromide is:
Chlordiazepoxide hydrochloride has been studied extensively in many species of animals and these studies are suggestive of action on the limbic system of the brain, which recent evidence indicates is involved in emotional responses. Hostile monkeys were made tame by oral drug doses, which did not cause sedation. Chlordiazepoxide hydrochloride revealed a “taming-action with the elimination of fear and aggression”. The taming effect of chlordiazepoxide hydrochloride was further demonstrated in rats made vicious by lesions in the septal area of the brain. The drug dosage which effectively blocked the vicious reaction was well below the dose which caused sedation in these animals.
The oral LD 50 of single doses of chlordiazepoxide hydrochloride, calculated according to the method of Miller and Tainter, is 720 mg/kg ± 51 mg/kg as determined in mice observed over a period of 5 days following dosage.
Clidinium bromide is an effective anticholinergic agent with activity approximating that of atropine sulfate against acetylcholine-induced spasms in isolated intestinal strips. On oral administration in mice, it proved an effective antisialagogue in preventing pilocarpine-induced salivation. Spontaneous intestinal motility in both rats and dogs is reduced following oral dosing with 0.1 mg/kg to 0.25 mg/kg. Potent cholinergic ganglionic blocking effects (vagal) were produced with intravenous usage in anesthetized dogs.
Oral doses of 2.5 mg/kg to dogs produced signs of nasal dryness and slight pupillary dilation. In two other species, monkeys and rabbits, doses of 5 mg/kg, po, given three times daily for 5 days did not produce apparent secretory or visual changes.
The oral LD 50 of single doses of clidinium bromide is 860 ± 57 mg/kg as determined in mice observed over a period of 5 days following dosage; the calculations were made according to the method of Miller and Tainter.
Effects on Reproduction
Reproduction studies in rats fed chlordiazepoxide hydrochloride, 10 mg/kg, 20 mg/kg and 80 mg/kg daily, and bred through one or two matings showed no congenital anomalies, nor were there adverse effects on lactation of the dams or growth of the newborn. However, in another study at 100 mg/kg daily there was noted a significant decrease in the fertilization rate and a marked decrease in the viability and body weight of offspring which may be attributable to sedative activity, thus resulting in lack of interest in mating and lessened maternal nursing and care of the young. One neonate in each of the first and second matings in the rat reproduction study at the 100 mg/kg dose exhibited major skeletal defects. Further studies are in progress to determine the significance of these findings.
Two series of reproduction experiments with clidinium bromide were carried out in rats, employing dosages of 2.5 mg/kg and 10 mg/kg daily in each experiment. In the first experiment, clidinium bromide was administered for a 9-week interval prior to mating; no untoward effect on fertilization or gestation was noted. The offspring were taken by caesarean section and did not show a significant incidence of congenital anomalies when compared to control animals. In the second experiment, adult animals were given clidinium bromide for 10 days prior to and through two mating cycles. No significant effects were observed on fertility, gestation, viability of offspring or lactation, as compared to control animals, nor was there a significant incidence of congenital anomalies in the offspring derived from these experiments.
A reproduction study of chlordiazepoxide hydrochloride and clidinium bromide capsules was carried out in rats through two successive matings. Oral daily doses were administered in two concentrations: 2.5 mg/kg chlordiazepoxide hydrochloride with 1.25 mg/kg clidinium bromide or 25 mg/kg chlordiazepoxide hydrochloride with 12.5 mg/kg clidinium bromide. In the first mating, no significant differences were noted between the control or the treated groups, with the exception of a slight decrease in the number of animals surviving during lactation among those receiving the highest dosage. As with all anticholinergic drugs, an inhibiting effect on lactation may occur. In the second mating, similar results were obtained except for a slight decrease in the number of pregnant females and in the percentage of offspring surviving until weaning. No congenital anomalies were observed in both matings in either the control or treated groups. Additional animal reproduction studies are in progress.
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